CN102212075A - Preparation method for cefbuperazone - Google Patents

Abstract

The invention relates to a preparation method for cefbuperazone, which comprises the following steps: A. carrying out methyl esterification on D-threonine; B. preparing DEPT-OMe; C. preparing DEPT-OMe-OP; and D. preparing DEPT-OP to obtain TBLZ-ester, carrying out one-step reaction to simultaneously remove two protection groups, and then salifying to obtain cefbuperazone. The preparation method has the advantages of few process steps, high yield, high purity of intermediate products of each step and target compounds, and low cost.

Description

The preparation method of cefbuperazone

Technical field

The present invention relates to a kind of preparation method of compound, particularly a kind of preparation method of cefbuperazone.

Background technology

The chemical synthesis process of cynnematin has a variety of, and application number is 200480014657.0, denomination of invention is the patent application of " cephalosporin compound "; Application number is 200710090501.3, denomination of invention is the patent application of " a kind of pharmaceutical composition, Its Preparation Method And Use "; Application number is 200710090958.4, denomination of invention is the patent application of " preparation method of T-1982 "; Application number is 200810123614.3, denomination of invention is the patent application of " process for purification of cefbuperazone intermediate "; " α one an amino β keto ester one β contains oxygen two skins) study on the synthesis ", Xu Yanjie, Chen Ligong, chemistry circular, 2004; " Design, Synthesis, and biological, evaluation ofbiotin-labeled (-)-ternatin, a potent fat-accumulation inhibitoragainst 3T3-L1 adipocytes " etc. document, all the chemical synthesis process of the plain class of cephalo is explored.

The preparation method of cefbuperazone mainly contains two kinds: 1. carry out 7 butt joints earlier, introduce methoxyl group again, then through removing 4 steps such as protecting group, get to embrace to the end and draw the ancestor.There is the processing condition harshness in this method, be difficult for realizing industrialization, and the introducing methoxyl group does not meet the best " the synthetic principle that converges " after butt joint; 2. introduce earlier methoxyl group, dock with side chain again, then through removing step such as protecting group; get to embrace to the end and draw the ancestor: with side chain and " female ring " intermediate of having introduced methoxyl group, i.e. " 7-MAC ", butt joint formation phthalein amido; after removing protecting group, get to embrace to the end and draw the ancestor then.These class methods are simple than the 1st class methods route, easily realize industrialization.It should be noted that and adopt these class methods, before 7 butt joints, need the protecting of side chain through base.But these class methods need to adopt f column chromatography purified method (extremely is eluent with benzene one acetate second) when 7 butt joints of preparation product intermediates, so just strengthened the difficulty of large-scale production inevitably, greatly increased preparation cost.

The T-1982 that utilizes aseptic freeze-dried technology to obtain, have on manufacturing process that the production unit requirement is too high, energy consumption is huge, production cost increases, be difficult to obtain uniform particles, flowability preferably the material form so that carry out defective such as packing; Utilize solvent crystallization manufactured T-1982, then exist T-1982 to be adsorbed on agitator and the reactor wall and cause defectives such as product can not separate with the form of " oily matter ".

Existing document is also mentioned the D-Threonine is protected with specific basic ether; its main method is to feed iso-butylene in the sulphuric acid soln of D-Threonine; generating hydroxyl and carboxyl is protected by tertbutyl ether simultaneously; in the end need to take off and use trifluoroacetic acid when protection is base; but industrial owing to use a large amount of sulfuric acid, environment there is bigger pollution.Therefore develop a kind of preparation method of reasonable cost-effective cefbuperazone, extremely urgent.

Summary of the invention

The object of the invention is to provide a kind of preparation method of compound; Another purpose of the present invention is to provide a kind of preparation method of cefbuperazone.

The present invention seeks to be achieved through the following technical solutions:

A kind of preparation method of cefbuperazone, this method is:

Steps A: with the esterification of D-Threonine;

The preparation of step B:DEPT-OMe;

The preparation of step C:DEPT-OMe-OP;

The preparation of step D:DEPT-OP.

Synthesis route of the present invention is as follows:

Synthesis route of the present invention is preferably:

Synthesis route of the present invention is preferably:

Synthesis route of the present invention also is preferably:

Among the preparation method of cefbuperazone of the present invention, steps A is chosen following a kind of method wantonly:

Steps A 1:D-Threonine adds anhydrous methanol, ice bath, and dripping thionyl chloride, stirred overnight at room temperature is concentrated into reaction solution dried, places and solidifies;

Perhaps steps A 2: anhydrous methanol, and ice bath, dripping thionyl chloride stirs, and disposable then adding D-Threonine refluxes and stirs, and reaction solution is concentrated into dried, places and solidifies.

Among the preparation method of cefbuperazone of the present invention, steps A is preferably as follows a kind of method:

Steps A 1:D-Threonine 1 weight part adds anhydrous methanol 1-150 weight part, ice bath, and dripping thionyl chloride 0.1-40 weight part, stirred overnight at room temperature is concentrated into reaction solution dried, places and solidifies;

Perhaps steps A 2: anhydrous methanol 1-150 parts by volume, and ice bath, dripping thionyl chloride 0.1-40 parts by volume stirred 20-40 minute, and disposable then adding D-Threonine 1 weight part reflux to stir 0.5-1.5 hour, reaction solution was concentrated into dried, placed and solidified.

Among the preparation method of cefbuperazone of the present invention, steps A is preferably as follows a kind of method:

Steps A 1:D-Threonine 50g adds anhydrous methanol 100ml, ice bath, and dripping thionyl chloride 30ml, stirred overnight at room temperature is concentrated into reaction solution dried, is directly used in step B; Product is a colourless transparent liquid, places to solidify;

Perhaps steps A 2: anhydrous methanol 100ml, and ice bath, dripping thionyl chloride 30ml stirred 30 minutes, and disposable then adding D-Threonine 50g reflux to stir 1 hour, reaction solution was concentrated into dried, was directly used in step B; Product is a colourless transparent liquid, places to solidify.

Among the preparation method of cefbuperazone of the present invention, step B chooses following a kind of method wantonly:

Step B1:D-THr-OMe-HCl adds entry, acetonitrile, and sodium bicarbonate, room temperature drips 0.1-2.1 equivalent/acetonitrile of DEPC, adds in 10-50 minute; Stirring at room finishes to reaction then, layering, and the upper strata is the organic layer of acetonitrile, and lower floor is a water layer, and water layer extracts with acetonitrile, merges organic layer, anhydrous sodium sulfate drying; Filter, decompression is taken off solvent and is obtained white solid;

Perhaps step B2: the acetonitrile among the B1 is replaced into methylene dichloride;

Perhaps step B3:D-THr-OMe-HCl, methylene dichloride, a triethylamine 1.5-3.5 equivalent, room temperature drips 0.1-2.1 equivalent/acetonitrile of DEPC, adds in 10-50 minute; Stirring at room to reaction finishes then, adds entry, layering, and the upper strata is a water layer, (extraction merges organic layer, anhydrous sodium sulfate drying to water layer with methylene dichloride; Filter, decompression is taken off solvent and is obtained white solid.

Among the preparation method of cefbuperazone of the present invention, step B is preferably as follows a kind of method:

Step B1:D-THr-OMe-HCl 20-40 weight part adds entry 50-150 parts by volume, acetonitrile 10-100 parts by volume, and each equivalent of sodium bicarbonate 1.5-3.5, room temperature drips 0.1-2.1 equivalent of DEPC/acetonitrile 10-100 parts by volume, adds in 10-50 minute; Stirring at room 0.5-1.5 hour then, layering, on become the organic layer of acetonitrile, lower floor is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile (100-300 parts by volume) * (2-6) extraction; Filter, decompression is taken off solvent and is obtained white solid;

Perhaps step B2: the acetonitrile 10-100 parts by volume among the B1 is replaced into methylene dichloride 10-100 parts by volume;

Perhaps step B3:D-THr-OMe-HCl 20-40 weight part, methylene dichloride 50-300 parts by volume, triethylamine 1.5-3.5 each equivalent, room temperature drips 0.1-2.1 equivalent of DEPC/acetonitrile 10-100 parts by volume, adds in 10-50 minute; Stirring at room 0.5-1.5 hour then, add entry 50-150 parts by volume, layering, the upper strata is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with methylene dichloride (100-300 parts by volume) * (2-6) extraction; Filter, decompression is taken off solvent and is obtained white solid.

Among the preparation method of cefbuperazone of the present invention, step B is preferably as follows a kind of method:

Step B1:D-THr-OMe-HCl 30g adds entry 100ml, acetonitrile 50ml, and sodium bicarbonate 2.5 each equivalent, room temperature drips DEPC1.1 equivalent/acetonitrile 50ml, adds in 30 minutes; Stirring at room is 1 hour then, layering, on become the organic layer of acetonitrile, lower floor is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid, yield 92.6%, and purity is greater than 96%;

Perhaps step B2: the acetonitrile 50ml among the B1 is replaced into methylene dichloride 50ml;

Perhaps step B3:D-THr-OMe-HCl 30g, methylene dichloride 150ml, 2.5 equivalents of triethylamine, room temperature drips DEPC1.1 equivalent/acetonitrile 50ml, adds in 30 minutes; Stirring at room is 1 hour then, adds entry 100ml, layering, and the upper strata is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with methylene dichloride 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid, yield 97.4%, and purity is greater than 96%.

Among the preparation method of cefbuperazone of the present invention, TPS among the step C, the optional following a kind of method of chlorosilanes such as TBS series:

Step C1:DEPT-OMe, 0.5-2.5 normal triethylamine or DIPEA, methylene dichloride is a solvent, drips 1.0-2.5 normal chlorosilane, and stirring at room to reaction finishes, add entry, separatory, the water layer dichloromethane extraction of equivalent, dried over sodium sulfate organic layer, take off solvent, product is directly used in step D;

Perhaps step C2:DEPT-OMe, the normal imidazoles of 0.5-2.5, DMF are solvent, drip 1.0-2.5 normal chlorosilane, stirring at room adds entry, separatory, the water layer dichloromethane extraction of equivalent, the dried over sodium sulfate organic layer is taken off solvent, and product is directly used in step D.

The described protecting group of taking off can be selected TBAF or 0.5-1.5: the trifluoroacetic acid/dichloromethane of 0.5-1.5 ratio.

Among the preparation method of cefbuperazone of the present invention, step C1 is preferably:

Step C1:DEPT-OMe, 0.5-2.5 normal triethylamine or DIPEA, methylene dichloride is a solvent, and making ratio is 0.5-1.5 weight part/3-7 parts by volume, drip 1.0-2.5 normal chlorosilane, stirring at room 0.5-1.5 hour, adding entry, to make ratio be 0.5-1.5 weight part/3-7 parts by volume, separatory, the dichloromethane extraction of water layer usefulness equivalent 2-4 time, the dried over sodium sulfate organic layer is taken off solvent, and product is directly used in step D.

Among the preparation method of cefbuperazone of the present invention, step C1 is preferably:

Step C1:DEPT-OMe, 1.5 normal triethylamine, methylene dichloride is a solvent, and making ratio is 1g/5ml, drip 1.1 normal chlorosilanes, stirring at room 1 hour, adding entry, to make ratio be 1g/5ml, separatory, the dichloromethane extraction of water layer usefulness equivalent 3 times, the dried over sodium sulfate organic layer is taken off solvent, and product is directly used in step D.

Among the preparation method of cefbuperazone of the present invention, step C2 is preferably:

Step C2:DEPT-OMe, the normal imidazoles of 0.5-2.5, DMF are solvent, making ratio is 0.5-1.5 weight part/3-7 parts by volume, drip 0.1-2.1 normal chlorosilane, stirring at room 0.5-1.5 hour, add entry, making ratio is 0.5-1.5 weight part/3-7 parts by volume, separatory, the dichloromethane extraction of water layer usefulness equivalent 2-4 time, dried over sodium sulfate organic layer, take off solvent, product is directly used in step D.

Among the preparation method of cefbuperazone of the present invention, step C2 is preferably:

Step C2:DEPT-OMe, 1.5 normal imidazoles, DMF are solvent, making ratio is 1g/5ml, drip 1.1 normal chlorosilanes, stirring at room 1 hour adds entry, making ratio is 1g/5ml, separatory, the dichloromethane extraction of water layer usefulness equivalent 3 times, dried over sodium sulfate organic layer, take off solvent, product is directly used in step D.

Among the preparation method of cefbuperazone of the present invention, THP among the step C, MIP become the guard method of ether series to be: step C3:DEPT-OMe, and methylene dichloride, the catalyst P TS of 1% weight ratio drips normal THP of 1.0-1.5 or MIP, stirred overnight at room temperature; Add 1% triethylamine then, add entry, layering, organic layer dried over sodium sulfate; Take off solvent promptly.

The described protecting group method of taking off can be selected 0.5-1.5: the trifluoroacetic acid/dichloromethane of 0.5-1.5 ratio or 0.5-1.5%HCl/MeOH.

Among the preparation method of cefbuperazone of the present invention, step C3 is preferably: DEPT-OMe, and methylene dichloride, the catalyst P TS of 1% weight ratio drips normal THP of 1.0-1.5 or MIP, stirred overnight at room temperature, 0-12 hour; Add the triethylamine of 0.5-1.5% then, add entry, making ratio is 0.5-1.5 weight part/3-7 parts by volume for making ratio, layering, organic layer dried over sodium sulfate; Take off solvent promptly.

Among the preparation method of cefbuperazone of the present invention, step C3 is preferably: DEPT-OMe, methylene dichloride, the catalyzer tosic acid of 1% weight ratio drips 1.2 normal THP, stirring at room 10 minutes, add then and be stirred to reaction behind 1% the triethylamine and finish, add entry, making ratio is 1g/5ml, layering, the organic layer dried over sodium sulfate; Take off solvent, get product, yield is at 83-98%; Purity is white solid greater than 95%.

Among the preparation method of cefbuperazone of the present invention, the guard method of benzylic ether is among the step C:

Step C4:DEPT-OMe, a salt of wormwood 0.5-2.5 equivalent, bromobenzyl or benzyl chloride, 90 ℃ are stirred to the reflection end, add entry, and dichloromethane extraction merges organic layer, the saturated common salt washing, dried over sodium sulfate, solvent evaporated adds sherwood oil, and is ultrasonic, filters, promptly.

Among the preparation method of cefbuperazone of the present invention, step C4 is preferably: DEPT-OMe, a salt of wormwood 0.5-2.5 equivalent, bromobenzyl or benzyl chloride, 0-90 ℃ was stirred 0-24 hour, and added entry, making ratio is 0.5-1.5 weight part/5-15 parts by volume, and 0.5-1.5 weight part/3-7 parts by volume dichloromethane extraction 2-4 time merges organic layer, saturated common salt washing 1-3 time, dried over sodium sulfate, solvent evaporated, add sherwood oil, making ratio is 0.5-1.5 weight part/3-7 parts by volume, ultrasonic 20-40 minute, filter, promptly.

Among the preparation method of cefbuperazone of the present invention, step C4 is preferably: DEPT-OMe, 1.5 equivalents of salt of wormwood, 1.2 equivalents of bromobenzyl or benzyl chloride, stirring at room 5 hours adds entry, making ratio is 1g/10ml, and 1g/5ml dichloromethane extraction 3 times merges organic layer, saturated common salt washing 2 times, dried over sodium sulfate, solvent evaporated, add sherwood oil, making ratio is 1g/5ml, ultrasonic 30 minutes, filter, obtain product; Yield 75-94%, purity is greater than 96%.

Among the preparation method of cefbuperazone of the present invention, step D chooses following a kind of preparation method wantonly:

Step D1: DEPT-OMe-OP is dissolved in the methyl alcohol, adds sodium hydroxide respectively, lithium hydroxide, yellow soda ash is hydrolyzed; The evaporate to dryness organic solvent adds entry, uses dichloromethane extraction, and phosphoric acid is transferred pH to 3-4, and dichloromethane extraction merges organic layer, dried over sodium sulfate; Promptly;

Perhaps step D2: DEPT-OMe-OP is dissolved in the methyl alcohol, adds sodium hydroxide respectively, equivalent hydrolysis of lithium hydroxide.

Among the preparation method of cefbuperazone of the present invention, step D is preferably as follows a kind of preparation method:

Step D1: DEPT-OMe-OP is dissolved in the methyl alcohol, and making ratio is 1g/5ml, adds sodium hydroxide respectively, lithium hydroxide, and yellow soda ash is hydrolyzed; Sodium hydroxide wherein, room temperature 1 hour; Lithium hydroxide, room temperature 1 hour; Yellow soda ash, 45 ℃, 3 hours; Solvent evaporated adds entry, and making ratio is 1g/10ml, uses 1g/10ml dichloromethane extraction 2 times, and phosphoric acid is transferred pH to 3-4, and 1g/10ml dichloromethane extraction 4-5 time merges organic layer, dried over sodium sulfate; Obtain product, yield 50-96%;

Perhaps step D2: DEPT-OMe-OP is dissolved in the methyl alcohol, and making ratio is 1g/5ml, adds sodium hydroxide respectively, equivalent hydrolysis of lithium hydroxide.

Among the preparation method of cefbuperazone of the present invention, step D is preferably as follows a kind of preparation method:

Step D1:DEPT-OMe-OTHP adds methyl alcohol (1g/5ml), stirs and makes dissolving, and 0 ℃ adds 1.0 equivalents of lithium hydroxide down, stirred 30 minutes; Add ether (1g/100ml) in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid, directly can be used for next step;

Perhaps step D2:DEPT-OMe-OTHP adds methyl alcohol (1g/5ml), stirs and makes dissolving, and 0 ℃ adds 1.0 equivalents of yellow soda ash down, stirred 30 minutes; Add ether (1g/100ml) in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid, directly can be used for next step.

TBLZ-ester can be according to prior art for preparing, and preferential selection mixes the acid anhydride method.

The TBLZ-ester deprotection prepares cefbuperazone acid can preferentially select trifluoroacetic acid/dichloromethane/methyl-phenoxide system according to prior art.

Cefbuperazone acid prepares the method for T-1982, and the present invention mentions with organic bases for the first time and preparing.General way: cefbuperazone acid is dissolved in organic solvent, as DMF, and DMA, methyl alcohol etc. add organic bases, as sodium acetate, Sodium isooctanoate etc.

The method that cefbuperazone acid prepares T-1982 is preferably: cefbuperazone acid adds DMA (1g/3ml), dissolving below 15 ℃, 1.2 normal Sodium isooctanoates of disposable adding, stirred 1 hour, and added Virahol (1g/10ml), stirred 2 hours, filter, filter cake is used acetone respectively, petroleum ether, and drying under reduced pressure below 15 ℃ promptly gets pure product.Yield 98.7%.

The described protecting group of taking off also can select Pd/C/MeOH to be palladium carbon methanol system;

When the preparation method of cefbuperazone of the present invention protects in chlorosilane series, the protection hydroxyl of preferred trimethylchlorosilane, wherein the cefbuperazone with the trimethylchlorosilane protection is to prepare as follows:

Steps A: with the esterification of D-Threonine

Under the condition of ice bath, in the three-necked bottle of the 250ml that the 100ml anhydrous methanol is housed, dripping thionyl chloride 30ml slowly, stirred 30 minutes the back, then at ice bath property adding next time D-Threonine 50g, refluxed 1 hour under agitation condition, reaction solution is concentrated into dried, is directly used in step B; Product is a colourless transparent liquid, places to solidify, and gets D-THr-OMe-HCl hydrochloride 71.9g, and yield is 99%;

The preparation of step B:DEPT-OMe

D-THr-OMe-HCl30g adds entry 100ml, methylene dichloride 50ml, and sodium bicarbonate 46.8g, room temperature slowly drips the acetonitrile 50ml solution of DEPCl 39.8g, adds in 30 minutes; Stirring at room is 1 hour then, and reaction finishes the reaction solution layering, on become the organic layer of acetonitrile, lower floor is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid 49.33g, yield 92.6%, and purity is greater than 96%;

The preparation of step C:DEPT-OMe-OTMS

DEPT-OMe 30.1g, be dissolved among the DMF of 150ml, add the 10.2g imidazoles, the back slowly drips trimethylchlorosilane 11.95g, room temperature condition stirred 1 hour down, reaction finishes, and adds entry 200ml in reaction solution, separatory, the dichloromethane extraction of water layer usefulness equivalent 3 times, the dried over sodium sulfate organic layer is taken off solvent, and product can be directly used in step D;

The preparation of step D:DEPT-OTMS;

Get DEPT-OMe-OTMS37.3g, add methyl alcohol 200ml stirring and make dissolving, 0 ℃ adds yellow soda ash 10.6g down, stirred 30 minutes; In reaction solution, add the ether of 1g/100ml, separate out solid, filter, the solid drying under reduced pressure, getting white solid is DEPT-OTMS, directly can be used for next step;

With the DEPT-OTMS 27.5g for preparing among the step D, be dissolved in the 1500ml methylene dichloride, add triethylamine 93g, be cooled to-20 ℃, drip the dichloromethane solution of Vinyl chloroformate, add 4.17g earlier, stirring at room 1 hour is utilized the high performance liquid chromatography monitoring reaction, calculate the consumption of Vinyl chloroformate with the peak area ratio of raw material according to the product intermediate, the Vinyl chloroformate 5.01g that adds then (0.0462mol, 0.6eq), so far, the DEPT-OTMS total overall reaction, be cooled to-20 ℃ once more, drip the methylene dichloride 1000ml solution of 7-MAC44.2g, 20 ℃ are stirred to mixed acid anhydride and 7-MAC completely dissolve; Add entry 1000ml, separatory, organic layer saturated sodium bicarbonate 500ml, each washing of water 500ml once, anhydrous sodium sulfate drying is taken off solvent under 20 ℃; The ethyl acetate petroleum ether recrystallization gets product TBLZ-ester, yield 82%;

With the TBLZ-ester100g for preparing, be dissolved among the methylene dichloride 300ml, add the mixing solutions of methyl-phenoxide 200ml and MeOH30ml, 0 ℃ drips trifluoroacetic acid 100ml down, being stirred to raw material disappears, add methyl tertiary butyl ether MTBE1000ml, separate out solid, filter, dry, obtain TBLZ-acid, be white crystal, yield 92%;

The TBLZ-acid10g that obtains is dissolved in dimethyl formamide 80ml, drips Sodium isooctanoate 2.92g, 10 ℃ were stirred 1.0 hours, add anhydrous isopropyl alcohol 100ml, stirred 1 hour, separate out a large amount of solids, filter, filter cake is placed on product then in the 100ml methyl tertiary butyl ether and stirred 1 hour with Virahol 100ml washing, filters, the product room temperature is dried, the room temperature decompressing and extracting is to weight then, yield 98%, and purity is 99.8%.

When the preparation method of cefbuperazone of the present invention protects hydroxyl in one-tenth ether series, the protection of preferred tetrahydropyrans, wherein the cefbuperazone with the trimethylchlorosilane protection is to prepare as follows:

Steps A: with the esterification of D-Threonine

D-Threonine 50g adds anhydrous methanol 100ml, dripping thionyl chloride 30ml under the condition of ice bath, and stirred overnight at room temperature is concentrated into reaction solution dried, is directly used in step B; Product is a colourless transparent liquid, places to solidify; Yield 100%;

The preparation of step B:DEPT-OMe

D-THr-OMe-HCl 30g adds entry 100ml, acetonitrile 50ml, and sodium bicarbonate 46.8g, room temperature slowly drips the acetonitrile 50ml solution of DEPCl 39.8g, adds in 30 minutes; Stirring at room is 1 hour then, and reaction finishes the reaction solution layering, on become the organic layer of acetonitrile, lower floor is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid 49.33g, yield 92.6%, and purity is greater than 96%;

The preparation of step C:DEPT-OMe-OTHP

DEPT-OMe is dissolved among the DMF, add the 10.2g imidazoles, it is TMSCl 11.95g that the back slowly drips trimethylchlorosilane, and room temperature condition stirred 1 hour down, and reaction finishes, in reaction solution, add entry 200ml, separatory, the dichloromethane extraction of water layer usefulness equivalent 3 times, dried over sodium sulfate organic layer, take off solvent, product can be directly used in step D;

The preparation of step D:DEPT-OTHP

Get DEPT-OMe-OTHP38.5g, add methyl alcohol 200ml stirring and make dissolving, 0 ℃ adds yellow soda ash 10.6g down, stirred 30 minutes; Add the ether of 1g/100ml in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid DEPT-OTHP, directly can be used for next step;

With the DEPT-OTHP 37.1g for preparing among the step D, be dissolved in the 1500ml methylene dichloride, add triethylamine 12.1g, be cooled to-20 ℃, drip the dichloromethane solution of Vinyl chloroformate, add 5.4g earlier, stirring at room 1 hour is utilized the high performance liquid chromatography monitoring reaction, calculates the consumption of Vinyl chloroformate with the peak area ratio of raw material according to the product intermediate, the Vinyl chloroformate 6.48g that adds then, so far, the DEPT-OTMS total overall reaction is cooled to-20 ℃ once more, drip the methylene dichloride 1000ml solution of 7-MAC52.3g, 20 ℃ are stirred to mixed acid anhydride and 7-MAC completely dissolve; Add entry 1000ml, separatory, organic layer saturated sodium bicarbonate 500ml, each washing of water 500ml once, anhydrous sodium sulfate drying is taken off solvent under 20 ℃; The ethyl acetate petroleum ether recrystallization gets product TBLZ-ester, yield 88.3%;

With the TBLZ-ester100g for preparing, be dissolved among the methylene dichloride 300ml, add the mixing solutions of methyl-phenoxide 200ml and MeOH30ml, 0 ℃ drips trifluoroacetic acid 100ml down, being stirred to raw material disappears, add methyl tertiary butyl ether MTBE1000ml, separate out solid, filter, dry, obtain TBLZ-acid, be white crystal, yield 92%;

The TBLZ-acid10g that obtains is dissolved in dimethyl formamide 80ml, drips Sodium isooctanoate 2.92g, 10 ℃ were stirred 1.0 hours, add anhydrous isopropyl alcohol 100ml, stirred 1 hour, separate out a large amount of solids, filter, filter cake washs with Virahol 100ml, and then product being placed on the 100ml methyl tertiary butyl ether is to stir 1 hour among the MTBE, filters, the product room temperature is dried, the room temperature decompressing and extracting is to weight then, yield 98%, and purity is 99.8%.

The preparation method of cefbuperazone of the present invention is when benzylic ether series protection hydroxyl, and preferably with the bromotoluene protection, wherein the cefbuperazone with the trimethylchlorosilane protection is to prepare as follows:

Steps A: with the esterification of D-Threonine

D-Threonine 50g (0.42mmol) adds anhydrous methanol 100ml, dripping thionyl chloride 30ml under the condition of ice bath, and stirred overnight at room temperature is concentrated into reaction solution dried, is directly used in step B; Product is a colourless transparent liquid, places to solidify; Yield 100%;

The preparation of step B:DEPT-OMe

D-THr-OMe-HCl 30g adds entry 100ml, acetonitrile 50ml, and sodium bicarbonate 46.8g, room temperature slowly drips the acetonitrile 50ml solution of DEPCl 39.8g, adds in 30 minutes; Stirring at room is 1 hour then, and reaction finishes the reaction solution layering, on become the organic layer of acetonitrile, lower floor is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid 49.33g, yield 92.6%, and purity is greater than 96%;

The preparation of step C:DEPT-OMe-OBz

DEPT-OMe 30.1g is dissolved among the DMF of 150ml, adds salt of wormwood 20.7g, bromobenzyl 20.5g, stirring at room reaction in 5 hours finishes, and adds entry 250ml in reaction solution, with dichloromethane extraction 3 times, merge organic layer, saturated common salt washing 2 times, dried over sodium sulfate, solvent evaporated adds sherwood oil, making ratio is 1g/5ml, ultrasonic 30 minutes, filter, obtain product; Yield 93.2%, purity 96.5%;

The preparation of step D:DEPT-OBz;

DEPT-OMe-OBz 40.5g stirs and makes it to be dissolved in 2000ml methyl alcohol, and 0 ℃ adds yellow soda ash 10.6g down, stirred 30 minutes; Add the ether of 1g/100ml in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid, directly can be used for next step;

With the DEPT-OBz 39.2g for preparing among the step D, be dissolved in the 1500ml methylene dichloride, add triethylamine 12.1g, be cooled to-20 ℃, drip the dichloromethane solution of Vinyl chloroformate, add 5.4g earlier, stirring at room 1 hour is utilized the high performance liquid chromatography monitoring reaction, calculates the consumption of Vinyl chloroformate with the peak area ratio of raw material according to the product intermediate, the Vinyl chloroformate 6.48g that adds then, so far, the DEPT-OTMS total overall reaction is cooled to-20 ℃ once more, drip the methylene dichloride 1000ml solution of 7-MAC52.3g, 20 ℃ are stirred to mixed acid anhydride and 7-MAC completely dissolve; Add entry 1000ml, separatory, organic layer saturated sodium bicarbonate 500ml, each washing of water 500ml once, anhydrous sodium sulfate drying is taken off solvent under 20 ℃; The ethyl acetate petroleum ether recrystallization gets product TBLZ-ester, yield 89.6%; With the TBLZ-ester 100g for preparing, be dissolved among the methylene dichloride 300ml, add the mixing solutions of methyl-phenoxide 200ml and MeOH30ml, 0 ℃ drips trifluoroacetic acid 100ml down, being stirred to raw material disappears, add methyl tertiary butyl ether MTBE1000ml, separate out solid, filter, dry, obtain TBLZ-acid, be white crystal, yield 92%;

The TBLZ-acid10g that obtains is dissolved in dimethyl formamide 80ml, drips Sodium isooctanoate 2.92g, 10 ℃ were stirred 1.0 hours, add anhydrous isopropyl alcohol 100ml, stirred 1 hour, separate out a large amount of solids, filter, filter cake washs with Virahol 100ml, and then product being placed on the 100ml methyl tertiary butyl ether is to stir 1 hour among the MTBE, filters, the product room temperature is dried, the room temperature decompressing and extracting is to weight then, yield 98%, and purity is 99.8%.

Preferred three technical schemes of the invention described above; used protecting group is the conventional reagent that uses; on price, exist outstanding advantage; the product purity of three kinds of protection acquisitions is higher simultaneously; stable yield; help the industrialization of this technology, make the present invention be different from prior art and have tangible technical superiority.

The pass of weight part/parts by volume of the present invention is g/ml.

Judge among the present invention that it is or/and silica gel thin-layer chromatography obtains the result by high performance liquid chromatography that reaction finishes.

Wherein, abbreviation of the present invention is explained as follows respectively:

D-Thr：(2R，3S)-2-amino-3-hydroxybutyric?acid

DEPC：4-ethyl-2，3-dioxopiperazine-1-carbonyl?chloride，

DEPT-OMe：(2R，3S)-methyl-2-(4-ethylpiperazine-1-carboxamido)-3-hydroxybutanoate

The hydroxyl protection thing of DEPT-OMe-OP:DEPT-OMe, P represents blocking group, as TBS, THP, MIP, Bz etc.

TBS: the dimethyl tertiary butyl is silica-based

Carboxylic acid after the hydrolysis of DEPT-OMe-OH:DEPT-OMe-OP:DEPT-OMe methyl esters

TBLZ-ester: the protection product of cefbuperazone acid, wherein the blocking group of hydroxyl is the prepared P of this patent, the protecting group of carboxyl is the benzhydrol ester

THP: THP trtrahydropyranyl

MIP:Methoxyisopropyl, the methoxyl group sec.-propyl

Bz: benzyl

MEN：2-methoxyethoxymethyl

PTS: tosic acid

DIPEA: diisopropylethylamine

TBAF: tetrabutyl ammonium fluoride

TMSCl: trimethylchlorosilane

Hydroxyl to the D-Threonine is protected; having document to use specific basic ether protects; its main method is to feed iso-butylene in the sulphuric acid soln of D-Threonine; generating hydroxyl and carboxyl is protected by tertbutyl ether simultaneously; in the end need to take off and use trifluoroacetic acid when protection is base; but it is industrial owing to use a large amount of sulfuric acid; environment there is bigger pollution; the present invention has developed a kind of environmentally friendly; production yield height; the hydroxyl protection mode that production cost is low successfully obtains the qualified product of cefbuperazone, and in industrial easily mass-produced.

Cefbuperazone preparation method of the present invention has overcome the defective that exists in the prior art, possesses following advantage simultaneously: every step yield is all very high, generally surpasses 90%; Every step products can be directly used in next step substantially without purifying, is beneficial to industry and recurs product; The reaction conditions gentleness, environmentally friendly; Last protecting group increases few to whole explained hereafter cost; The deprotection mild condition can be general with the condition of the benzhydrol protecting group of taking off 7-MAC, once can take off 2 protecting groups, and the acid of product cefbuperazone can be separated out from reaction system, and protecting group is stayed in the reaction solution.The cefbuperazone acid that obtains has very high purity (generally greater than 97%).

Of the present inventionly prepare the method for T-1982 with organic bases, its advantage is: the productive rate height; Unnecessary organic bases can be stayed in the solution, not polluted product; Service temperature is low, does not need heating.

Following experimental example and embodiment are used to further specify the present invention, but are not limited to the present invention.

Experimental example 1

The method for preparing cefbuperazone in experimental technique of the present invention and the prior art is compared as follows:

(1) the present invention adopt cheap protecting group THP (11000 yuan/t), TBS (117000 yuan/t), iso-butylene (13700 yuan/t) all very cheap, the use of THP report not in the prior art particularly;

(2) the present invention is a homogeneous reaction in the step that obtains product, can improve speed of response greatly, has reduced the reaction times, it is more complete to be that reaction is carried out, and save cost, and this step condition of prior art is the solid-liquid two-phase, react very incomplete, cause raw material to remain in a large number.

(3) used protecting group THP (11000/t); TBS (117000/t); iso-butylene (13700/t) can be taken off with same condition is disposable by the DMP (diphenyl-carbinol) with the protecting group among the 7-MAC when the deprotection base; step and production cost have been saved; the protecting group of taking off can be stayed in the reaction solution; and product is separated out with the solid form, separates easily, only needs simple filtering promptly can obtain the higher cephalo of purity and draws total acid.

Experimental example 2

Embodiment of the invention moderate purity measuring method is all with reference to 2005 editions second sections of Chinese Pharmacopoeia, appendix VD item high effective liquid chromatography for measuring.

Embodiment

Embodiment 1 steps A: the esterification of D-Threonine prepares Thr-OMe-HCl

D-Threonine 50g adds anhydrous methanol 100ml, ice bath, and dripping thionyl chloride 30ml, stirred overnight at room temperature is concentrated into reaction solution dried, is directly used in step B; Product is a colourless transparent liquid, places to solidify, and gets Thr-OMe--HCl 71.2g, and yield is 100%, MS (M+1)=170.61.

Embodiment 2 steps A: the esterification of D-Threonine is prepared Thr-OMe-HCl

Anhydrous methanol 100ml, ice bath, dripping thionyl chloride 30ml stirred 30 minutes, and disposable then adding L-Threonine 50g reflux to stir 1 hour, reaction solution was concentrated into dried, was directly used in step B; Product is a colourless transparent liquid, place solidify Thr-OMe-HCl 71.2g, yield is 100%, MS (M+1)=170.61.

The preparation of embodiment 3 step B:DEPT-OMe

D-THr-OMe-HCl 30g adds entry 100ml, acetonitrile 50ml, and 2.5 equivalents of sodium bicarbonate, room temperature drips 1.1 equivalent 39.7g/ of DEPC acetonitrile 50ml, adds in 30 minutes; Stirring at room is 1 hour then, layering, on become the organic layer of acetonitrile, lower floor is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid 49.3g, yield 92.6%, and purity is 97.9%, MS (M+1)=302.3, ¹HNMR (DMSO-d ₆, ppm) δ: 1.18 (s, 3H), 1.35 (t, J=9Hz, 3H), 3.36 (m, 2H), 3.42 (m, 2H), 3.58 (s, 1H) 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.65 (m, 1H), 6.02 (s, 1H).

The preparation of embodiment 4 step B:DEPT-OMe

D-THr-OMe-HCl 30g adds entry 100ml, methylene dichloride 50ml, and sodium bicarbonate 2.5 each equivalent, room temperature drips DEPC1.1 equivalent 39.7g/ acetonitrile 50ml, adds in 30 minutes; Stirring at room is 1 hour then, layering, on become the organic layer of acetonitrile, lower floor is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid 49.3g, yield 92.6%, and purity is 96.2%, MS (M+1)=302.3 is a same substance through silica gel thin-layer chromatography stratographic analysis and embodiment 3.

The preparation of embodiment 5 step B:DEPT-OMe

D-THr-OMe-HCl 30g, methylene dichloride 150ml, 2.5 equivalents of triethylamine, room temperature drips DEPC1.1 equivalent/acetonitrile 50ml, adds in 30 minutes; Stirring at room is 1 hour then, adds entry 100ml, layering, and the upper strata is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with methylene dichloride 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid 51.9g, yield 97.4%, and purity is 98.2%, is same substance through silica gel thin-layer chromatography stratographic analysis and embodiment 3.

The preparation of embodiment 6 step C:DEPT-OMe-OTMS

DEPT-OMe, 1.5 normal triethylamine, methylene dichloride is a solvent, and making ratio is 1g/5ml, drip 1.1 normal trimethylchlorosilanes (TMSCl), stirring at room 1 hour, adding entry, to make ratio be 1g/5ml, separatory, the dichloromethane extraction of water layer usefulness equivalent 3 times, the dried over sodium sulfate organic layer is taken off solvent, and product is directly used in step D; MS (M+1)=374.2, ¹HNMR (DMSO-d ₆, ppm) δ: 0.21 (s, 9H), 1.18 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 3.35-3.42 (m, 4H), 3.68 (s, 3H), 3.75 (c, J=9Hz, 2H), 4.50 (m, 1H), 4.64 (m, 1H), 6.02 (s, 1H).

The preparation of embodiment 7 step C:DEPT-OMe-OP (TPS, chlorosilane series such as TBS)

DEPT-OMe, 1.5 normal imidazoles, DMF are solvent, making ratio is 1g/5ml, drip 1.1 normal trimethylchlorosilanes (TMSCl), stirring at room 1 hour adds entry, making ratio is 1g/5ml, separatory, the dichloromethane extraction of water layer usefulness equivalent 3 times, dried over sodium sulfate organic layer, take off solvent, product is directly used in step D; Through silica gel thin-layer chromatography stratographic analysis and embodiment 6 is same substance MS (M+1)=374.2, ¹HNMR (DMSO-d ₆, ppm) δ: 0.21 (s, 9H), 1.18 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 3.35-3.42 (m, 4H), 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.64 (m, 1H), 6.02 (s, 1H).

The preparation of embodiment 8 step C:DEPT-OMe-OTMS (TPS, chlorosilane series such as TBS)

DEPT-OMe, 1.5 normal imidazoles, DMF are solvent, making ratio is 1g/5ml, drip 1.1 normal trimethylchlorosilanes (TMSCl), stirring at room 1 hour adds entry, making ratio is 1g/5ml, separatory, the dichloromethane extraction of water layer usefulness equivalent 3 times, dried over sodium sulfate organic layer, take off solvent, product is directly used in step D; Through silica gel thin-layer chromatography stratographic analysis and embodiment 6 is same substance MS (M+1)=374.2, ¹HNMR (DMSO-d ₆, ppm) δ: 0.21 (s, 9H), 1.18 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 3.35-3.42 (m, 4H), 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.64 (m, 1H), 6.02 (s, 1H).

The preparation of embodiment 9 step C:DEPT-OMe-OTHP (THP, MIP becomes ether series)

DEPT-OMe, methylene dichloride, the catalyzer tosic acid of 1% weight ratio drips 1.2 normal THP, and stirring at room 10 minutes adds 1% triethylamine then, adds entry, and making ratio is 1g/5ml, layering, organic layer dried over sodium sulfate; Take off solvent, get water white transparency oily thing, yield is 100%%; Purity is 97.8%, MS (M+1)=386.4, ¹HNMR (DMSO-d ₆, ppm) δ: 1.18 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 1.59-1.65 (m, 6H), 3.35-3.42 (m, 4H), 3.55-3.62 (m, 2H), 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.27 (m, 1H), 4.74 (m, 1H), 4.95 (m, 1H), 6.02 (s, 1H).

The preparation of embodiment 10 step C:DEPT-OMe-OBz (benzylic ether series)

DEPT-OMe, 1.5 equivalents of salt of wormwood, 1.2 equivalents of bromobenzyl or benzyl chloride, stirring at room 5 hours adds entry, and making ratio is 1g/10ml, 1g/5ml dichloromethane extraction 3 times merges organic layer, saturated common salt washing 2 times, dried over sodium sulfate, solvent evaporated adds sherwood oil, making ratio is 1g/5ml, ultrasonic 30 minutes, filters, obtaining white solid is that yield is 93.6%; Purity is 97.4%, MS (M+1)=392.39, ¹HNMR (DMSO-d ₆, ppm): δ: 1.18 (d, J=7Hz, 3H), 1.35 (t, J=9Hz, 3H), 3.35-3.43 (m, 4H), 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.27 (m, 1H), 4.61 (s, 2H), 4.74 (m, 1H), 6.02 (s, 1H), 7.38 (m, 3H), 7.45 (m, 2H).

The preparation of embodiment 11 step D:DEPT-OTHP:

DEPT-OMe-OTHP adds methyl alcohol (1g/5ml), stirs and makes dissolving, and 0 ℃ adds 1.0 equivalents of lithium hydroxide down, stirred 30 minutes; Add ether (1g/100ml) in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid, and yield is all greater than 96.3%; Purity directly can be used for next step greater than 98.6%, MS (M+1)=372.41, ¹HNMR (DMSO-d ₆, ppm) δ: 1.18 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 1.59-1.65 (m, 6H), 3.35-3.42 (m, 4H), 3.55-3.62 (m, 2H), 3.75 (d, J=9Hz, 2H), 4.27 (m, 1H), 4.74 (m, 1H), 4.95 (m, 1H), 6.02 (s, 1H).9.42(s，1H)。

The preparation of embodiment 12 step D:DEPT-OTHP

DEPT-OMe-OTHP adds methyl alcohol (1g/5ml), stirs and makes dissolving, and 0 ℃ adds 1.0 equivalents of yellow soda ash down, stirred 30 minutes; Add ether (1g/100ml) in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid, and yield is all greater than 95%; Purity directly can be used for next step all greater than 97.4%.Be shown in embodiment 11 through silica gel thin-layer chromatography and have identical Rf value and process mass spectrum and nucleus magnetic hydrogen spectrum affirmation.MS(M+1)＝372.41， ¹HNMR(DMSO-d ₆，ppm)δ：1.18(d，J＝7Hz，3H)，1.38(t，J＝9Hz，3H)，1.59-1.65(m，6H)，3.35-3.42(m，4H)，3.55-3.62(m，2H)，3.75(d，J＝9Hz，2H)，4.27(m，1H)，4.74(m，1H)，4.95(m，1H)，6.02(s，1H)。9.42(s，1H)。

The preparation method of embodiment 13 T-1982s:

Cefbuperazone acid 10g, add N,N-DIMETHYLACETAMIDE (DMA) (1g/3ml), 15 ℃ of dissolvings, 1.2 normal Sodium isooctanoates of disposable adding, 0-10 ℃ was stirred 1 hour, add Virahol (1g/10ml), stirred 2 hours, filter, filter cake is used acetone respectively, petroleum ether, the white crystal 10.35g of 15 ℃ of drying under reduced pressure, yield 100%; Purity is 99.6%.MS(M+1)＝628.65； ¹HNMR(DMSO-d ₆，ppm)：δ：1.18(s，3H)，1.35(t，J＝9Hz，3H)，3.08-3.16(m，2H)，3.30(s，3H)，3.36(m，2H)，3.42(m，2H)，3.63(s，2H)，3.75(d，J＝9Hz，2H)，3.95(s，3H)，4.24(m，1H)，4.61(m，1H)，4.85(m，1H)，5.4(m，1H)，6.01(s，1H)，6.55(s，1H)，8.01(s，1NH)，12.5(s，1H)。

Embodiment 14

Steps A: the esterification of D-Threonine is prepared Thr-OMe-HCl

D-Threonine 50g adds anhydrous methanol 100ml, ice bath, and dripping thionyl chloride 30ml, stirred overnight at room temperature, reaction finishes, and reaction solution is concentrated into dried, is directly used in step B; Product is a colourless transparent liquid, place solidify Thr-OMe-HCl 70.65g, yield is greater than 99.2%, MS (M+1)=170.61.

The preparation of step B:DEPT-OMe

D-THr-OMe-HCl 30g adds entry 100ml, acetonitrile 50ml, and 2.5 equivalents of sodium bicarbonate, room temperature drips DEPC1.1 equivalent/acetonitrile 50ml, adds in 30 minutes; Stirring at room is 1 hour then, becomes the organic layer of acetonitrile in the layering, and lower floor is a water layer, and water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid 49.5g, yield 92.6%, and purity is greater than 96%; MS (M+1)=302.3, ¹HNMR (DMSO-d ₆, ppm) δ: 1.18 (s, 3H), 1.35 (t, J=9Hz, 3H), 3.36 (m, 2H), 3.42 (m, 2H), 3.58 (s, 1H) 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.65 (m, 1H), 6.02 (s, 1H).

The preparation of step C:DEPT-OMe-OTMS (TPS, chlorosilane series such as TBS)

DEPT-OMe, 1.5 normal triethylamine, methylene dichloride is a solvent, and making ratio is 1g/5ml, drip 1.1 equivalent trimethylchlorosilanes (TMSCl), stirring at room 1 hour, adding entry, to make ratio be 1g/5ml, separatory, the dichloromethane extraction of water layer usefulness equivalent 3 times, the dried over sodium sulfate organic layer is taken off solvent, and product is directly used in step D; MS (M+1)=374.2, ¹HNMR (DMSO-d ₆, ppm) δ: 0.21 (s, 9H), 1.18 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 3.35-3.42 (m, 4H), 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.64 (m, 1H), 6.02 (s, 1H).

The preparation of step D:DEPT-OTMS

DEPT-OMe-OTMS adds methyl alcohol (1g/5ml), stirs and makes dissolving, and 0 ℃ adds 1.0 equivalents of yellow soda ash down, stirred 30 minutes; Add ether (1g/100ml) in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid, directly can be used for next step MS (M+1)=360.45, ¹HNMR (DMSO-d ₆, ppm) δ: 0.21 (s, 9H), 1.27 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 3.35-3.42 (m, 2H), 3.75 (d, J=9Hz, 2H), 4.27 (m, 1H), 4.74 (m, 1H), 6.02 (s, 1H), 12.53 (s, 1H).

Embodiment 15

Steps A: with the esterification of D-Threonine

Anhydrous methanol 100ml, ice bath, dripping thionyl chloride 30ml stirred 30 minutes, and disposable then adding D-Threonine 50g reflux to stir 1 hour, reaction solution was concentrated into dried, was directly used in step B; Product is a colourless transparent liquid, places to solidify; MS (M+1)=170.61.

The preparation of step B:DEPT-OMe

D-THr-OMe-HCl 30g adds entry 100ml, methylene dichloride 50ml, and sodium bicarbonate 2.5 each equivalent, room temperature drips DEPC1.1 equivalent/acetonitrile 50ml, adds in 30 minutes; Stirring at room is 1 hour then, layering, on become the organic layer of acetonitrile, lower floor is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid, yield 92.6%, and purity is greater than 96%; MS (M+1)=302.3, ¹HNMR (DMSO-d ₆, ppm) δ: 1.18 (s, 3H), 1.35 (t, J=9Hz, 3H), 3.36 (m, 2H), 3.42 (m, 2H), 3.58 (s, 1H) 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.65 (m, 1H), 6.02 (s, 1H).

The preparation of step C:DEPT-OMe-OTMS (TPS, chlorosilane series such as TBS)

DEPT-OMe, 1.5 normal imidazoles, DMF are solvent, making ratio is 1g/5ml, drips 1.1 normal trimethylchlorosilanes (TMSCl), stirring at room 1 hour, add entry, making ratio is 1g/5ml, separatory, the dichloromethane extraction of water layer usefulness equivalent 3 times, the dried over sodium sulfate organic layer is taken off solvent, and product can be directly used in step D, MS (M+1)=374.2 ¹HNMR (DMSO-d ₆, ppm) δ: 0.21 (s, 9H), 1.18 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 3.35-3.42 (m, 4H), 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.64 (m, 1H), 6.02 (s, 1H).。

The preparation of step D:DEPT-OTMS;

DEPT-OMe-OTMS adds methyl alcohol (1g/5ml), stirs and makes dissolving, and 0 ℃ adds 1.0 equivalents of yellow soda ash down, stirred 30 minutes; Add ether (1g/100ml) in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid, directly can be used for next step.MS(M+1)＝360.45， ¹HNMR(DMSO-d ₆，ppm)δ：0.21(s，9H)，1.27(d，J＝7Hz，3H)，1.38(t，J＝9Hz，3H)，3.35-3.42(m，2H)，3.75(d，J＝9Hz，2H)，4.27(m，1H)，4.74(m，1H)，6.02(s，1H)，12.53(s，1H)。

Embodiment 16

Steps A: with the esterification of D-Threonine

Anhydrous methanol 100ml, ice bath, dripping thionyl chloride 30ml stirred 30 minutes, and disposable then adding D-Threonine 50g reflux to stir 1 hour, reaction solution was concentrated into dried, was directly used in step B; Product is a colourless transparent liquid, places to solidify;

The preparation of step B:DEPT-OMe

D-THr-OMe-HCl 30g, methylene dichloride 150ml, 2.5 equivalents of triethylamine, room temperature drips 1.1 equivalents of DEPC/acetonitrile 50ml, adds in 30 minutes; Stirring at room is 1 hour then, adds entry 100ml, layering, and the upper strata is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with methylene dichloride 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid, yield 97.4%, and purity is greater than 96%; MS (M+1)=302.3 ¹HNMR (DMSO-d ₆, ppm): δ: 1.18 (s, 3H), 1.35 (t, J=9Hz, 3H), 3.36 (m, 2H), 3.42 (m, 2H), 3.58 (s, 1H) 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.65 (m, 1H), 6.02 (s, 1H).

The preparation of step C:DEPT-OMe-OTMS (TPS, chlorosilane series such as TBS)

DEPT-OMe, 1.5 normal imidazoles, DMF are solvent, making ratio is 1g/5ml, drip 1.1 normal trimethylchlorosilanes (TMSCl), stirring at room 1 hour adds entry, making ratio is 1g/5ml, separatory, the dichloromethane extraction of water layer usefulness equivalent 3 times, dried over sodium sulfate organic layer, take off solvent, product is directly used in step D; MS (M+1)=374.2, ¹HNMR (DMSO-d ₆, ppm) δ: 0.21 (s, 9H), 1.18 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 3.35-3.42 (m, 4H), 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.64 (m, 1H), 6.02 (s, 1H).

The preparation of step D:DEPT-OTMS;

DEPT-OMe-OTMS adds methyl alcohol (1g/5ml), stirs and makes dissolving, and 0 ℃ adds 1.0 equivalents of yellow soda ash down, stirred 30 minutes; Add ether (1g/100ml) in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid, directly can be used for next step, MS (M+1)=360.45, ¹HNMR (DMSO-d ₆, ppm) δ: 0.21 (s, 9H), 1.27 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 3.35-3.42 (m, 2H), 3.75 (d, J=9Hz, 2H), 4.27 (m, 1H), 4.74 (m, 1H), 6.02 (s, 1H), 12.53 (s, 1H).

Embodiment 17

Steps A: with the esterification of D-Threonine

D-Threonine 50g adds anhydrous methanol 100ml, ice bath, and dripping thionyl chloride 30ml, stirred overnight at room temperature is concentrated into reaction solution dried, is directly used in step B; Product is a colourless transparent liquid, places to solidify; MS (M+1)=170.61;

The preparation of step B:DEPT-OMe

D-THr-OMe-HCl 30g adds entry 100ml, acetonitrile 50ml, and sodium bicarbonate 2.5 each equivalent, room temperature drips DEPC1.1 equivalent/acetonitrile 50ml, adds in 30 minutes; Stirring at room is 1 hour then, layering, on become the organic layer of acetonitrile, lower floor is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid, yield 92.6%, and purity is greater than 96%; MS (M+1)=302.3; ¹HNMR (DMSO-d ₆, ppm): δ: 1.18 (s, 3H), 1.35 (t, J=9Hz, 3H), 3.36 (m, 2H), 3.42 (m, 2H), 3.58 (s, 1H) 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.65 (m, 1H), 6.02 (s, 1H).

The preparation of step C:DEPT-OMe-OTHP (THP, MIP becomes ether series)

DEPT-OMe, methylene dichloride, the catalyzer tosic acid of 1% weight ratio drips 1.2 normal THP, and stirring at room 10 minutes adds 1% triethylamine then, adds entry, and making ratio is 1g/5ml, layering, organic layer dried over sodium sulfate; Take off solvent, get product, yield is at 83-98%; Purity is white solid greater than 95%; MS (M+1)=386.4, ¹HNMR (DMSO-d ₆, ppm) δ: 1.18 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 1.59-1.65 (m, 6H), 3.35-3.42 (m, 4H), 3.55-3.62 (m, 2H), 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.27 (m, 1H), 4.74 (m, 1H), 4.95 (m, 1H), 6.02 (s, 1H).

The preparation of step D:DEPT-OTHP

DEPT-OMe-OTHP adds methyl alcohol (1g/5ml), stirs and makes dissolving, and 0 ℃ adds 1.0 equivalents of yellow soda ash down, stirred 30 minutes; Add ether (1g/100ml) in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid, directly can be used for next step, MS (M+1)=372.41, ¹HNMR (DMSO-d ₆, ppm) δ: 1.18 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 1.59-1.65 (m, 6H), 3.35-3.42 (m, 4H), 3.55-3.62 (m, 2H), 3.75 (d, J=9Hz, 2H), 4.27 (m, 1H), 4.74 (m, 1H), 4.95 (m, 1H), 6.02 (s, 1H).9.42(s，1H)。

Embodiment 18

Steps A: with the esterification of D-Threonine

Anhydrous methanol 100ml, ice bath, dripping thionyl chloride 30ml stirred 30 minutes, and disposable then adding D-Threonine 50g reflux to stir 1 hour, reaction solution was concentrated into dried, was directly used in step B; Product is a colourless transparent liquid, places to solidify; MS (M+1)=170.61;

The preparation of step B:DEPT-OMe

D-THr-OMe-HCl 30g, methylene dichloride 150ml, 2.5 equivalents of triethylamine, room temperature drips DEPC1.1 equivalent/acetonitrile 50ml, adds in 30 minutes; Stirring at room is 1 hour then, adds entry 100ml, layering, and the upper strata is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with methylene dichloride 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid, yield 97.4%, and purity is greater than 96%; MS (M+1)=302.3; ¹HNMR (DMSO-d ₆, ppm): δ: 1.18 (s, 3H), 1.35 (t, J=9Hz, 3H), 3.36 (m, 2H), 3.42 (m, 2H), 3.58 (s, 1H) 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.65 (m, 1H), 6.02 (s, 1H).

The preparation of step C:DEPT-OMe-OBz (benzylic ether series)

DEPT-OMe, 1.5 equivalents of salt of wormwood, 1.2 equivalents of bromobenzyl or benzyl chloride, stirring at room 5 hours adds entry, and making ratio is 1g/10ml, 1g/5ml dichloromethane extraction 3 times merges organic layer, saturated common salt washing 2 times, dried over sodium sulfate, solvent evaporated adds sherwood oil, making ratio is 1g/5ml, ultrasonic 30 minutes, filter, obtain product; Yield 75-94%, purity is greater than 96%; MS (M+1)=392.42, ¹HNMR (DMSO-d ₆, ppm): δ: 1.18 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 3.42-3.62 (m, 4H), 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.27 (m, 1H), 4.64 (s, 2H), 4.74 (m, 1H), 6.02 (s, 1H), 7.38 (m, 3H), 7.45 (m, 2H).

The preparation of step D:DEPT-OBz;

DEPT-OMe-OBz adds methyl alcohol (1g/5ml), stirs and makes dissolving, and 0 ℃ adds 1.0 equivalents of yellow soda ash down, stirred 30 minutes; Add ether (1g/100ml) in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid, directly can be used for next step, MS (M+1)=378.4, ¹HNMR (DMSO-d ₆, ppm) δ: 1.18 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 3.35-3.43 (m, 4H), 3.75 (d, J=9Hz, 2H), 4.27 (m, 1H), 4.61 (s, 2H), 4.74 (m, 1H), 6.02 (s, 1H), 7.38 (m, 3H), 7.45 (m, 2H), 12.57 (s, 1H).

Embodiment 19

Steps A: with the esterification of D-Threonine

Anhydrous methanol 100ml, ice bath, dripping thionyl chloride 30ml stirred 30 minutes, and disposable then adding D-Threonine 50g reflux to stir 1 hour, reaction solution was concentrated into dried, was directly used in step B; Product is a colourless transparent liquid, places to solidify; MS (M+1)=170.61;

The preparation of step B:DEPT-OMe

D-THr-OMe-HCl 30g adds entry 100ml, methylene dichloride 50ml, and sodium bicarbonate 2.5 each equivalent, room temperature drips DEPC1.1 equivalent/acetonitrile 50ml, adds in 30 minutes; Stirring at room is 1 hour then, layering, on become the organic layer of acetonitrile, lower floor is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid, yield 92.6%, and purity is greater than 96%; MS (M+1)=302.3, ¹HNMR (DMSO-d ₆, ppm): δ: 1.18 (s, 3H), 1.35 (t, J=9Hz, 3H), 3.36 (m, 2H), 3.42 (m, 2H), 3.58 (s, 1H) 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.65 (m, 1H), 6.02 (s, 1H).

The preparation of step C:DEPT-OMe-OTMS (TPS, chlorosilane series such as TBS)

DEPT-OMe, 1.5 normal imidazoles, DMF are solvent, making ratio is 1g/5ml, drip 1.1 normal trimethylchlorosilanes (TMSCl), stirring at room 1 hour adds entry, making ratio is 1g/5ml, separatory, the dichloromethane extraction of water layer usefulness equivalent 3 times, dried over sodium sulfate organic layer, take off solvent, product is directly used in step D; MS (M+1)=374.2, ¹HNMR (DMSO-d ₆, ppm) δ: 0.21 (s, 9H), 1.18 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 3.35-3.42 (m, 4H), 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.64 (m, 1H), 6.02 (s, 1H).。

The preparation of step D:DEPT-OTMS;

DEPT-OMe-OTMS adds methyl alcohol (1g/5ml), stirs and makes dissolving, and 0 ℃ adds 1.0 equivalents of yellow soda ash down, stirred 30 minutes; Add ether (1g/100ml) in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid, directly can be used for next step; MS (M+1)=360.45, ¹HNMR (DMSO-d ₆, ppm) δ: 0.21 (s, 9H), 1.27 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 3.35-3.42 (m, 2H), 3.75 (d, J=9Hz, 2H), 4.27 (m, 1H), 4.74 (m, 1H), 6.02 (s, 1H), 12.53 (s, 1H).

The preparation method of T-1982

Cefbuperazone acid adds DMA (1g/3ml), the following dissolving of 15 degree, and 1.2 normal Sodium isooctanoates of disposable adding stirred 1 hour, add Virahol (1g/10ml), stirred 2 hours, filter, filter cake is used acetone respectively, petroleum ether, and drying under reduced pressure below 15 ℃ promptly gets pure product; Yield 98.7%.

Embodiment 20

Steps A: with the esterification of D-Threonine

D-Threonine 50g adds anhydrous methanol 100ml, ice bath, and dripping thionyl chloride 30ml, stirred overnight at room temperature is concentrated into reaction solution dried, is directly used in step B; Product is a colourless transparent liquid, places to solidify; MS (M+1)=170.61;

The preparation of step B:DEPT-OMe

D-THr-OMe-HCl 30g adds entry 100ml, acetonitrile 50ml, and sodium bicarbonate 2.5 each equivalent, room temperature drips DEPC1.1 equivalent/acetonitrile 50ml, adds in 30 minutes; Stirring at room is 1 hour then, layering, on become the organic layer of acetonitrile, lower floor is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid, yield 92.6%, and purity is greater than 96%; MS (M+1)=302.3, ¹HNMR (DMSO-d ₆, ppm): δ: 1.18 (s, 3H), 1.35 (t, J=9Hz, 3H), 3.36 (m, 2H), 3.42 (m, 2H), 3.58 (s, 1H) 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.65 (m, 1H), 6.02 (s, 1H).

The preparation of step C:DEPT-OMe-OP (THP, MIP becomes ether series)

DEPT-OMe, methylene dichloride, the catalyzer tosic acid of 1% weight ratio drips 1.2 normal THP, and stirring at room 10 minutes adds 1% triethylamine then, adds entry, and making ratio is 1g/5ml, layering, organic layer dried over sodium sulfate; Take off solvent, get product, yield is at 83-98%; Purity is white solid greater than 95%; MS (M+1)=386.4, ¹HNMR (DMSO-d ₆, ppm) δ: 1.18 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 1.59-1.65 (m, 6H), 3.35-3.42 (m, 4H), 3.55-3.62 (m, 2H), 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.27 (m, 1H), 4.74 (m, 1H), 4.95 (m, 1H), 6.02 (s, 1H).

The preparation of step D:DEPT-OTHP

DEPT-OMe-OTHP adds methyl alcohol (1g/5ml), stirs and makes dissolving, and 0 ℃ adds 1.0 equivalents of yellow soda ash down, stirred 30 minutes; Add ether (1g/100ml) in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid, directly can be used for next step; MS (M+1)=372.41, ¹HNMR (DMSO-d ₆, ppm) δ: 1.18 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 1.59-1.65 (m, 6H), 3.35-3.42 (m, 4H), 3.55-3.62 (m, 2H), 3.75 (d, J=9Hz, 2H), 4.27 (m, 1H), 4.74 (m, 1H), 4.95 (m, 1H), 6.02 (s, 1H).9.42(s，1H)。

The preparation method of T-1982

Cefbuperazone acid adds DMA (1g/3ml), dissolving below 15 ℃, and 1.2 normal Sodium isooctanoates of disposable adding stirred 1 hour, add Virahol (1g/10ml), stirred 2 hours, filter, filter cake is used acetone respectively, petroleum ether, and drying under reduced pressure below 15 ℃ promptly gets pure product; Yield 98.7% obtains solid and measures through acidic leach and obtain data and be: MS (M+1)=627.6, ¹HNMR (DMSO-d ₆, ppm): δ: 1.18 (s, 3H), 1.35 (t, J=9Hz, 3H), 3.08-3.16 (m, 2H), 3.36 (m, 2H), 3.42 (m, 2H), 3.30 (s, 3H), 3.60 (s, 4H), 3.75 (d, J=9Hz, 2H), 4.61 (m, 1H), 4.80 (m, 1OH), 5.40 (s, 1H), 8.54 (s, 1H), 8.0 (s, 1NH), 12.5 (s, 1H).

Embodiment 21

Steps A: with the esterification of D-Threonine

Anhydrous methanol 100ml, ice bath, dripping thionyl chloride 30ml stirred 30 minutes, and disposable then adding D-Threonine 50g reflux to stir 1 hour, reaction solution was concentrated into dried, was directly used in step B; Product is a colourless transparent liquid, places to solidify; MS (M+1)=170.61;

The preparation of step B:DEPT-OMe

D-THr-OMe-HCl 30g, methylene dichloride 150ml, 2.5 equivalents of triethylamine, room temperature drips DEPC1.1 equivalent/acetonitrile 50ml, adds in 30 minutes; Stirring at room is 1 hour then, adds entry 100ml, layering, and the upper strata is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with methylene dichloride 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid, yield 97.4%, and purity is greater than 96%; MS (M+1)=302.3 ¹HNMR (DMSO-d ₆, ppm): δ: 1.18 (s, 3H), 1.35 (t, J=9Hz, 3H), 3.36 (m, 2H), 3.42 (m, 2H), 3.58 (s, 1H) 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.65 (m, 1H), 6.02 (s, 1H).

The preparation of step C:DEPT-OMe-OBz (benzylic ether series)

DEPT-OMe, 1.5 equivalents of salt of wormwood, 1.2 equivalents of bromobenzyl or benzyl chloride, stirring at room 5 hours adds entry, and making ratio is 1g/10ml, 1g/5ml dichloromethane extraction 3 times merges organic layer, saturated common salt washing 2 times, dried over sodium sulfate, solvent evaporated adds sherwood oil, making ratio is 1g/5ml, ultrasonic 30 minutes, filter, obtain product; Yield 75-94%, purity is greater than 96%; MS (M+1)=392.39, ¹HNMR (DMSO-d ₆, ppm): δ: 1.18 (d, J=7Hz, 3H), 1.35 (t, J=9Hz, 3H), 3.35-3.43 (m, 4H), 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.27 (m, 1H), 4.61 (s, 2H), 4.74 (m, 1H), 6.02 (s, 1H), 7.38 (m, 3H), 7.45 (m, 2H).

The preparation of step D:DEPT-OTHP;

DEPT-OMe-OTHP adds methyl alcohol (1g/5ml), stirs and makes dissolving, and 0 ℃ adds 1.0 equivalents of yellow soda ash down, stirred 30 minutes; Add ether (1g/100ml) in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid, directly can be used for next step; MS (M+1)=372.41, ¹HNMR (DMSO-d ₆, ppm) δ: 1.18 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 1.59-1.65 (m, 6H), 3.35-3.42 (m, 4H), 3.55-3.62 (m, 2H), 3.75 (d, J=9Hz, 2H), 4.27 (m, 1H), 4.74 (m, 1H), 4.95 (m, 1H), 6.02 (s, 1H).9.42(s，1H)。

Embodiment 22

Steps A: with the esterification of D-Threonine

Under the condition of ice bath, in the three-necked bottle of the 250ml that the 100ml anhydrous methanol is housed, dripping thionyl chloride 30ml slowly, stirred 30 minutes the back, then at the ice bath D-Threonine 50g of property adding next time (0.42mmol), under agitation condition, refluxed 1 hour, and reaction solution was concentrated into dried, be directly used in step B; Product is a colourless transparent liquid, places to solidify, and gets D-THr-OMe-HCl hydrochloride 71.9g, and yield is 100%; MS (M+1)=170.61.

The preparation of step B:DEPT-OMe

D-THr-OMe-HCl 30g (0.177mol) adds entry 100ml, methylene dichloride 50ml, sodium bicarbonate 46.8g (0.442mol, 2.5eq), room temperature, slowly drip DEPC139.8g (0.195mol, acetonitrile 1.1eq) (50ml) solution added in 30 minutes; Stirring at room is 1 hour then, and reaction finishes the reaction solution layering, on become the organic layer of acetonitrile, lower floor is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid 49.33g, yield 92.6%, and purity is greater than 96%; MS (M+1)=302.3, ¹HNMR (DMSO-d ₆, ppm) δ: 1.18 (s, 3H), 1.35 (t, J=9Hz, 3H), 3.36 (m, 2H), 3.42 (m, 2H), 3.58 (s, 1H) 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.65 (m, 1H), 6.02 (s, 1H).

The preparation of step C:DEPT-OMe-OTMS (TPS, chlorosilane series such as TBS)

DEPT-OMe 30.1g (0.1mol) is dissolved among the DMF of 150ml, adds 10.2g (1.5mol) imidazoles, the back slowly drips trimethylchlorosilane (TMSCl) 11.95g (0.11mol), and room temperature condition stirred 1 hour down, and reaction finishes, in reaction solution, add entry 200ml, separatory, the dichloromethane extraction of water layer usefulness equivalent 3 times, dried over sodium sulfate organic layer, take off solvent, product can be directly used in step D, MS (M+1)=374.2 ¹HNMR (DMSO-d ₆, ppm) δ: 0.21 (s, 9H), 1.18 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 3.35-3.42 (m, 4H), 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.64 (m, 1H), 6.02 (s, 1H).

The preparation of step D:DEPT-OTMS;

Get DEPT-OMe-OTMS37.3g (0.1mol), add methyl alcohol 200ml stirring and make dissolving, 0 ℃ adds yellow soda ash 10.6g (0.1mol) down, stirred 30 minutes; Add ether (1g/100ml) in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid, directly can be used for next step.MS(M+1)＝360.45， ¹HNMR(DMSO-d ₆，ppm)δ：0.21(s，9H)，1.27(d，J＝7Hz，3H)，1.38(t，J＝9Hz，3H)，3.35-3.42(m，2H)，3.75(d，J＝9Hz，2H)，4.27(m，1H)，4.74(m，1H)，6.02(s，1H)，12.53(s，1H)。

With the DEPT-OTMS 27.5g (0.077mol) for preparing among the step D, be dissolved in the 1500ml methylene dichloride, add triethylamine 93g (0.092mol, 1.2eq), be cooled to-20 ℃, drip the dichloromethane solution of Vinyl chloroformate, the adding 4.17g of elder generation (0.0385mol, 0.5eq), stirring at room 1 hour, utilize the high performance liquid chromatography monitoring reaction, according to the consumption of product intermediate with the peak area ratio calculating Vinyl chloroformate of raw material, and the Vinyl chloroformate 5.01g that adds then (0.0462mol, 0.6eq), so far, the DEPT-OTMS total overall reaction is cooled to-20 ℃ once more, drips 7-MAC44.2g (0.0847mol, 1.1eq) methylene dichloride (1000ml) solution, 20 ℃ are stirred to and mix acid anhydride and 7-MAC completely dissolve.Add entry 1000ml, separatory, organic layer saturated sodium bicarbonate 500ml, each washing of water 500ml once, anhydrous sodium sulfate drying is taken off solvent under 20 ℃.The ethyl acetate petroleum ether recrystallization gets product TBLZ-ester, yield 82%.MS(M+1)＝867.05； ¹HNMR(DMSO-d ₆，ppm)：δ：0.21(s，9H)，1.29(s，3H)，1.35(t，J＝9Hz，3H)，3.08-3.16(m，2H)，3.30(s，3H)，3.36(m，2H)，3.42(m，2H)，3.60(s，2H)，3.75(d，J＝9Hz，2H)，3.98(s，3H)，4.24(m，1H)，4.61(m，1H)，5.40(s，1H)，6.0(s，1H)6.53(m，1H)，7.36-7.38(m，10H)，8.54(s，1H)，8.05(s，1NH)。

With the TBLZ-ester100g (0.116mol) for preparing, be dissolved among the methylene dichloride 300ml, add the mixing solutions of methyl-phenoxide (200ml) and MeOH (30ml), 0 ℃ drips trifluoroacetic acid 100ml down, being stirred to raw material disappears, add methyl tertiary butyl ether MTBE1000ml, separate out solid, filter, dry, obtain TBLZ-acid, be white crystal, yield 92%.MS(M+1)＝628.65； ¹HNMR(DMSO-d ₆，ppm)：δ：1.18(s，3H)，1.35(t，J＝9Hz，3H)，3.08-3.16(m，2H)，3.30(s，3H)，3.36(m，2H)，3.42(m，2H)，3.63(s，2H)，3.75(d，J＝9Hz，2H)，3.95(s，3H)，4.24(m，1H)，4.61(m，1H)，4.85(m，1H)，5.4(m，1H)，6.01(s，1H)，6.55(s，1H)，8.01(s，1NH)，12.5(s，1H)。

The TBLZ-acid10g (0.016mol) that obtains is dissolved in dimethyl formamide (DMF) 80ml, and dropping Sodium isooctanoate 2.92g (0.0176mol, 1.1eq), 10 ℃ were stirred 1.0 hours, added anhydrous isopropyl alcohol 100ml, stirred 1 hour, separate out a large amount of solids, filter, filter cake washs with Virahol 100ml, then product is placed in the 100ml methyl tertiary butyl ether (MTBE) and stirred 1 hour, filter, the product room temperature is dried, and the room temperature decompressing and extracting is to weight then, yield 98%, purity are 99.8%; Obtaining solid measures through acidic leach and obtains data and be: MS (M+1)=628.65; ¹HNMR (DMSO-d ₆, ppm): δ: 1.18 (s, 3H), 1.35 (t, J=9Hz, 3H), 3.08-3.16 (m, 2H), 3.30 (s, 3H), 3.36 (m, 2H), 3.42 (m, 2H), 3.63 (s, 2H), 3.75 (d, J=9Hz, 2H), 3.95 (s, 3H), 4.24 (m, 1H), 4.61 (m, 1H), 4.85 (m, 1H), 5.4 (m, 1H), 6.01 (s, 1H), 6.55 (s, 1H), 8.01 (s, 1NH), 12.5 (s, 1H).

Embodiment 23

Steps A: with the esterification of D-Threonine

D-Threonine 50g (0.42mmol) adds anhydrous methanol 100ml, dripping thionyl chloride 30ml under the condition of ice bath, and stirred overnight at room temperature is concentrated into reaction solution dried, is directly used in step B; Product is a colourless transparent liquid, places to solidify; Yield 100%, MS (M+1)=170.61;

The preparation of step B:DEPT-OMe

D-THr-OMe-HCl 30g (0.177mol) adds entry 100ml, acetonitrile 50ml, sodium bicarbonate 46.8g (0.442mol, 2.5eq), room temperature, slowly drip DEPCl 39.8g (0.195mol, acetonitrile 1.1eq) (50ml) solution added in 30 minutes; Stirring at room is 1 hour then, and reaction finishes the reaction solution layering, on become the organic layer of acetonitrile, lower floor is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid 49.33g, yield 92.6%, and purity is greater than 96%; MS (M+1)=302.3; ¹HNMR (DMSO-d ₆, ppm): δ: 1.18 (s, 3H), 1.35 (t, J=9Hz, 3H), 3.36 (m, 2H), 3.42 (m, 2H), 3.58 (s, 1H) 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.65 (m, 1H), 6.02 (s, 1H).

The preparation of step C:DEPT-OMe-OTHP (THP, MIP becomes ether series)

DEPT-OMe is dissolved among the DMF, add 10.2g (1.5mol) imidazoles, the back slowly drips trimethylchlorosilane (TMSCl) 11.95g (0.11mol), and room temperature condition stirred 1 hour down, reaction finishes, in reaction solution, add entry 200ml, separatory, the dichloromethane extraction of water layer usefulness equivalent 3 times, the dried over sodium sulfate organic layer, take off solvent, product can be directly used in step D, MS (M+1)=386.41; ¹HNMR (DMSO-d ₆, ppm) δ: 1.18 (d, J=7Hz, 3H), 1.38 (t, J=7Hz, 3H), 1.59-1.65 (m, 6H), 3.35-3.42 (m, 2H), and 3.55-3.62 (m, 2H), 3.55-3.65 (m, 2H), 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.27 (m, 1H), 4.74 (m, 1H), 4.95 (m, 1H), 6.02 (s, 1H).

The preparation of step D:DEPT-OTHP

Get DEPT-OMe-OTHP38.5g (0.1mol), add methyl alcohol 200ml stirring and make dissolving, 0 ℃ adds yellow soda ash 10.6g (0.1mol) down, stirred 30 minutes; Add ether (1g/100ml) in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid DEPT-OTHP, directly can be used for next step, MS (M+1)=372.39, ¹HNMR (DMSO-d ₆, ppm): δ: 1.18 (d, J=7Hz, 3H), 1.38 (t, J=7Hz, 3H), 1.55-1.65 (m, 6H), 3.35-3.42 (m, 4H), and 3.55-3.62 (m, 2H), 3.75 (d, J=9Hz, 2H), 3.96 (m, 1H), 4.78 (m, 1H), 4.95 (m, 1H), 6.02 (s, 1H), 9.42 (s, 1H).

With the DEPT-OTHP 37.1g (0.1mol) for preparing among the step D, be dissolved in the 1500ml methylene dichloride, add triethylamine 12.1g (0.12mol, 1.2eq), be cooled to-20 ℃, drip the dichloromethane solution of Vinyl chloroformate, the adding 5.4g of elder generation (0.05mol, 0.5eq), stirring at room 1 hour, utilize the high performance liquid chromatography monitoring reaction, according to the consumption of product intermediate with the peak area ratio calculating Vinyl chloroformate of raw material, and the Vinyl chloroformate 6.48g that adds then (0.06mol, 0.6eq), so far, the DEPT-OTMS total overall reaction is cooled to-20 ℃ once more, drips 7-MAC52.3g (0.11mol, 1.1eq) methylene dichloride (1000ml) solution, 20 ℃ are stirred to and mix acid anhydride and 7-MAC completely dissolve.Add entry 1000ml, separatory, organic layer saturated sodium bicarbonate 500ml, each washing of water 500ml once, anhydrous sodium sulfate drying is taken off solvent under 20 ℃.The ethyl acetate petroleum ether recrystallization gets product TBLZ-ester, yield 88.3%.MS(M+1)＝878.99， ¹HNMR(DMSO-d ₆，ppm)：δ：1.18(s，3H)，1.35(t，J＝9Hz，3H)，1.55-1.65(m，6H)，3.08-3.16(m，2H)，3.30(s，3H)，3.36(m，2H)，3.42(m，2H)，3.55-3.65(m，2H)，3.60(s，2H)，3.75(d，J＝9Hz，2H)，3.86(m，1H)，3.95(s，3H)，4.85(m，1H)，4.95(m，1H)，5.40(s，1H)，6.05(s，1H)，6.53(m，1H)，7.36-7.38(m，10H)，8.0(s，1NH)。

With the TBLZ-ester100g (0.114mol) for preparing, be dissolved among the methylene dichloride 300ml, add the mixing solutions of methyl-phenoxide (200ml) and MeOH (30ml), 0 ℃ drips trifluoroacetic acid 100ml down, being stirred to raw material disappears, add methyl tertiary butyl ether MTBE1000ml, separate out solid, filter, dry, obtain TBLZ-acid, be white crystal, yield 92%.MS(M+1)＝628.65； ¹HNMR(DMSO-d ₆，ppm)：δ：1.18(s，3H)，1.35(t，J＝9Hz，3H)，3.08-3.16(m，2H)，3.30(s，3H)，3.36(m，2H)，3.42(m，2H)，3.63(s，2H)，3.75(d，J＝9Hz，2H)，3.95(s，3H)，4.24(m，1H)，4.61(m，1H)，4.85(m，1H)，5.4(m，1H)，6.01(s，1H)，6.55(s，1H)，8.01(s，1NH)，12.5(s，1H)。

The TBLZ-acid10g (0.016mol) that obtains is dissolved in dimethyl formamide (DMF) 80ml, and dropping Sodium isooctanoate 2.92g (0.0176mol, 1.1eq), 10 ℃ were stirred 1.0 hours, added anhydrous isopropyl alcohol 100ml, stirred 1 hour, separate out a large amount of solids, filter, filter cake washs with Virahol 100ml, then product is placed in the 100ml methyl tertiary butyl ether (MTBE) and stirred 1 hour, filter, the product room temperature is dried, and the room temperature decompressing and extracting is to weight then, yield 98%, purity are 99.8%; Obtaining solid measures through acidic leach and obtains data and be: MS (M+1)=628.65; ¹HNMR (DMSO-d ₆, ppm): δ: 1.18 (s, 3H), 1.35 (t, J=9Hz, 3H), 3.08-3.16 (m, 2H), 3.30 (s, 3H), 3.36 (m, 2H), 3.42 (m, 2H), 3.63 (s, 2H), 3.75 (d, J=9Hz, 2H), 3.95 (s, 3H), 4.24 (m, 1H), 4.61 (m, 1H), 4.85 (m, 1H), 5.4 (m, 1H), 6.01 (s, 1H), 6.55 (s, 1H), 8.01 (s, 1NH), 12.5 (s, 1H).

Embodiment 24

Steps A: with the esterification of D-Threonine

D-Threonine 50g (0.42mmol) adds anhydrous methanol 100ml, dripping thionyl chloride 30ml under the condition of ice bath, and stirred overnight at room temperature is concentrated into reaction solution dried, is directly used in step B; Product is a colourless transparent liquid, places to solidify; Yield 100%, MS (M+1)=170.61;

The preparation of step B:DEPT-OMe

D-THr-OMe-HCl 30g (0.177mol) adds entry 100ml, acetonitrile 50ml, sodium bicarbonate 46.8g (0.442mol, 2.5eq), room temperature, slowly drip DEPCl 39.8g (0.195mol, acetonitrile 1.1eq) (50ml) solution added in 30 minutes; Stirring at room is 1 hour then, and reaction finishes the reaction solution layering, on become the organic layer of acetonitrile, lower floor is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid 49.33g, yield 92.6%, and purity is greater than 96%; MS (M+1)=302.3; ¹HNMR (DMSO-d ₆, ppm): δ: 1.18 (s, 3H), 1.35 (t, J=9Hz, 3H), 3.36 (m, 2H), 3.42 (m, 2H), 3.58 (s, 1H) 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.50 (m, 1H), 4.65 (m, 1H), 6.02 (s, 1H).

The preparation of step C:DEPT-OMe-OBz (benzylic ether series)

DEPT-OMe 30.1g (0.1mol) is dissolved among the DMF of 150ml, adds salt of wormwood 20.7g (0.15mol) bromobenzyl 20.5g (0.12mol), stirring at room reaction in 5 hours finishes, and adds entry 250ml in reaction solution, uses dichloromethane extraction 3 times, merge organic layer, saturated common salt washing 2 times, dried over sodium sulfate, solvent evaporated, add sherwood oil, making ratio is 1g/5ml, ultrasonic 30 minutes, filter, obtain product; Yield 93.2%, purity 96.5%; MS (M+1)=392.39, ¹HNMR (DMSO-d ₆, ppm): δ: 1.18 (d, J=7Hz, 3H), 1.35 (t, J=9Hz, 3H), 3.35-3.43 (m, 4H), 3.68 (s, 3H), 3.75 (d, J=9Hz, 2H), 4.27 (m, 1H), 4.61 (s, 2H), 4.74 (m, 1H), 6.02 (s, 1H), 7.38 (m, 3H), 7.45 (m, 2H).

The preparation of step D:DEPT-OBz;

DEPT-OMe-OBz 40.5g (0.1mol) stirs and makes it to be dissolved in 2000ml methyl alcohol, and 0 ℃ adds yellow soda ash 10.6g (0.1mol) down, stirred 30 minutes; Add ether (1g/100ml) in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid, directly can be used for next step; MS (M+1)=378.4, ¹HNMR (DMSO-d ₆, ppm) δ: 1.18 (d, J=7Hz, 3H), 1.38 (t, J=9Hz, 3H), 3.35-3.43 (m, 4H), 3.75 (d, J=9Hz, 2H), 4.27 (m, 1H), 4.61 (s, 2H), 4.74 (m, 1H), 6.02 (s, 1H), 7.38 (m, 3H), 7.45 (m, 2H), 12.57 (s, 1H).

With the DEPT-OBz 39.2g (0.1mol) for preparing among the step D, be dissolved in the 1500ml methylene dichloride, add triethylamine 12.1g (0.12mol, 1.2eq), be cooled to-20 ℃, drip the dichloromethane solution of Vinyl chloroformate, the adding 5.4g of elder generation (0.05mol, 0.5eq), stirring at room 1 hour, utilize the high performance liquid chromatography monitoring reaction, according to the consumption of product intermediate with the peak area ratio calculating Vinyl chloroformate of raw material, and the Vinyl chloroformate 6.48g that adds then (0.06mol, 0.6eq), so far, the DEPT-OTMS total overall reaction is cooled to-20 ℃ once more, drips 7-MAC52.3g (0.11mol, 1.1eq) methylene dichloride (1000ml) solution, 20 ℃ are stirred to and mix acid anhydride and 7-MAC completely dissolve.Add entry 1000ml, separatory, organic layer saturated sodium bicarbonate 500ml, each washing of water 500ml once, anhydrous sodium sulfate drying is taken off solvent under 20 ℃.The ethyl acetate petroleum ether recrystallization gets product TBLZ-ester, yield 89.6%.MS(M+1)＝884.99， ¹HNMR(DMSO-d ₆，ppm)：δ：1.18(s，3H)，1.35(t，J＝9Hz，3H)，3.08-3.16(m，2H)，3.36(m，2H)，3.42(m，2H)，3.30(s，3H)，3.60(s，2H)，3.75(d，J＝9Hz，2H)，3.85(m，1H)，3.95(s，3H)，4.63(m，2H)，4.83(s，1H)，5.40(s，1H)，6.05(m，1H)，6.53(m，1H)，7.36-7.47(m，15H)，8.05(s，1NH)。

With the TBLZ-ester 100g (0.114mol) for preparing, be dissolved among the methylene dichloride 300ml, add the mixing solutions of methyl-phenoxide (200ml) and MeOH (30ml), 0 ℃ drips trifluoroacetic acid 100ml down, being stirred to raw material disappears, add methyl tertiary butyl ether MTBE1000ml, separate out solid, filter, dry, obtain TBLZ-acid, be white crystal, yield 92%.MS(M+1)＝628.65； ¹HNMR(DMSO-d ₆，ppm)：δ：1.18(s，3H)，1.35(t，J＝9Hz，3H)，1.59-1.62(m，6H)，3.08-3.16(m，2H)，3.30(s，3H)，3.36(m，2H)，3.42(m，2H)，3.63(s，2H)，3.55-3.66(m，2H)，3.75(d，J＝9Hz，2H)，3.86(m，1H)，3.95(s，3H)，4.85(m，1H)，4.95(m，1H)，6.55(s，1H)，7.36-7.38(m，10H)，8.01(s，1NH)，8.54(s，1H)，12.5(s，1H)。

The TBLZ-acid10g (0.016mol) that obtains is dissolved in dimethyl formamide (DMF) 80ml, and dropping Sodium isooctanoate 2.92g (0.0176mol, 1.1eq), 10 ℃ were stirred 1.0 hours, added anhydrous isopropyl alcohol 100ml, stirred 1 hour, separate out a large amount of solids, filter, filter cake washs with Virahol 100ml, then product is placed in the 100ml methyl tertiary butyl ether (MTBE) and stirred 1 hour, filter, the product room temperature is dried, and the room temperature decompressing and extracting is to weight then, yield 98%, purity are 99.8%; Obtaining solid measures through acidic leach and obtains data and be: MS (M+1)=628.65; ¹HNMR (DMSO-d ₆, ppm): δ: 1.18 (s, 3H), 1.35 (t, J=9Hz, 3H), 1.59-1.62 (m, 6H), 3.08-3.16 (m, 2H), 3.30 (s, 3H), 3.36 (m, 2H), 3.42 (m, 2H), 3.63 (s, 2H), 3.55-3.66 (m, 2H), 3.75 (d, J=9Hz, 2H), 3.86 (m, 1H), 3.95 (s, 3H), 4.85 (m, 1H), 4.95 (m, 1H), 6.55 (s, 1H), 7.36-7.38 (m, 10H), 8.01 (s, 1NH), 8.54 (s, 1H), 12.5 (s, 1H).

Claims (8)

1. the preparation method of cefbuperazone is characterized in that this method is: steps A: with the esterification of D-Threonine; The preparation of step B:DEPT-OMe; The preparation of step C:DEPT-OMe-OP; The preparation of step D:DEPT-OP.

2. the preparation method of cefbuperazone as claimed in claim 1 is characterized in that the optional following a kind of method of steps A in this method:

Steps A 1:D-Threonine 50g adds anhydrous methanol 100ml, ice bath, and dripping thionyl chloride 30ml, stirred overnight at room temperature is concentrated into reaction solution dried, is directly used in step B; Product is a colourless transparent liquid, places to solidify;

Perhaps steps A 2: anhydrous methanol 100ml, and ice bath, dripping thionyl chloride 30ml stirred 30 minutes, and disposable then adding D-Threonine 50g reflux to stir 1 hour, reaction solution was concentrated into dried, was directly used in step B; Product is a colourless transparent liquid, places to solidify.

3. preparation method as claimed in claim 1 is characterized in that the optional following a kind of method of step B in this method:

Step B1:D-THr-OMe-HCl 30g adds entry 100ml, acetonitrile 50ml, and sodium bicarbonate 2.5 each equivalent, room temperature drips DEPCl.1 equivalent/acetonitrile 50ml, adds in 30 minutes; Stirring at room is 1 hour then, layering, on become the organic layer of acetonitrile, lower floor is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid;

Step B2: the acetonitrile 50ml among the B1 is replaced into methylene dichloride 50ml;

Step B3:D-THr-OMe-HCl 30g, methylene dichloride 150ml, 2.5 equivalents of triethylamine, room temperature drips DEPCl.1 equivalent/acetonitrile 50ml, adds in 30 minutes; Stirring at room is 1 hour then, adds entry 100ml, layering, and the upper strata is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with methylene dichloride 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid.

4. preparation method as claimed in claim 1 is characterized in that step C is optional following a kind of method in this method:

Step C1:DEPT-OMe, 1.5 normal triethylamine, methylene dichloride is a solvent, and making ratio is 1g/5ml, drip 1.1 normal chlorosilanes, stirring at room 1 hour, adding entry, to make ratio be 1 gram/5ml, separatory, the dichloromethane extraction of water layer usefulness equivalent 3 times, the dried over sodium sulfate organic layer is taken off solvent, and product is directly used in step D;

Step C2:DEPT-OMe, 1.5 normal imidazoles, DMF are solvent, making ratio is 1g/5ml, drip 1.1 normal chlorosilanes, stirring at room 1 hour adds entry, making ratio is 1g/5ml, separatory, the dichloromethane extraction of water layer usefulness equivalent 3 times, dried over sodium sulfate organic layer, take off solvent, product is directly used in step D;

Step C3:DEPT-OMe, methylene dichloride, the catalyzer tosic acid of 1% weight ratio drips 1.2 normal THP, and stirring at room 10 minutes adds 1% triethylamine then, adds entry, and making ratio is 1g/5ml, layering, organic layer dried over sodium sulfate; Take off solvent, get product;

Step C4:DEPT-OMe, 1.5 equivalents of salt of wormwood, 1.2 equivalents of bromobenzyl or benzyl chloride, stirring at room 5 hours adds entry, and making ratio is 1g/10ml, 1g/5ml dichloromethane extraction 3 times merges organic layer, saturated common salt washing 2 times, dried over sodium sulfate, solvent evaporated adds sherwood oil, making ratio is 1g/5ml, ultrasonic 30 minutes, filter, obtain product.

5. preparation method as claimed in claim 1 is characterized in that step D preparation method is:

Step D1:DEPT-OMe-OP, it is 1g/5ml that adding methyl alcohol makes ratio, stirs and makes dissolving, 0 ℃ adds 1.0 equivalents of lithium hydroxide down, stirred 30 minutes; Adding ether in reaction solution, to make ratio be 1g/100ml, separates out solid, filter, the solid drying under reduced pressure, white solid, directly can be used for next step;

Step D2:DEPT-OMe-OP, it is 1g/5ml that adding methyl alcohol makes ratio, stirs and makes dissolving, 0 ℃ adds 1.0 equivalents of yellow soda ash down, stirred 30 minutes; Adding ether in reaction solution, to make ratio be 1g/100ml, separates out solid, filter, the solid drying under reduced pressure, white solid, directly can be used for next step.

6. preparation method as claimed in claim 1 is characterized in that cefbuperazone is to prepare as follows:

Steps A: with the esterification of D-Threonine

Under the condition of ice bath, in the three-necked bottle of the 250ml that the 100ml anhydrous methanol is housed, dripping thionyl chloride 30ml slowly, stirred 30 minutes the back, then at ice bath property adding next time D-Threonine 50g, refluxed 1 hour under agitation condition, reaction solution is concentrated into dried, is directly used in step B; Product is a colourless transparent liquid, places to solidify, and gets the D-THr-OMe-HCl hydrochloride;

The preparation of step B:DEPT-OMe

D-THr-OMe-HCl30g adds entry 100ml, methylene dichloride 50ml, and sodium bicarbonate 46.8g, room temperature slowly drips the acetonitrile 50ml solution of DEPCl 39.8g, adds in 30 minutes; Stirring at room is 1 hour then, and reaction finishes the reaction solution layering, on become the organic layer of acetonitrile, lower floor is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid;

The preparation of step C:DEPT-OMe-OTMS

DEPT-OMe 30.1g, be dissolved among the DMF of 150ml, add the 10.2g imidazoles, the back slowly drips trimethylchlorosilane 11.95g, room temperature condition stirred 1 hour down, reaction finishes, and adds entry 200ml in reaction solution, separatory, the dichloromethane extraction of water layer usefulness equivalent 3 times, the dried over sodium sulfate organic layer is taken off solvent, and product can be directly used in step D;

The preparation of step D:DEPT-OTMS;

Get DEPT-OMe-OTMS37.3g, add methyl alcohol 200ml stirring and make dissolving, 0 ℃ adds yellow soda ash 10.6g down, stirred 30 minutes; In reaction solution, add the ether of 1g/100ml, separate out solid, filter, the solid drying under reduced pressure, getting white solid is DEPT-OTMS, directly can be used for next step;

With the DEPT-OTMS 27.5g for preparing among the step D, be dissolved in the 1500ml methylene dichloride, add triethylamine 93g, be cooled to-20 ℃, drip the dichloromethane solution of Vinyl chloroformate, add 4.17g earlier, stirring at room 1 hour is utilized the high performance liquid chromatography monitoring reaction, calculates the consumption of Vinyl chloroformate with the peak area ratio of raw material according to the product intermediate, the Vinyl chloroformate 0.0462mol that adds then, 0.6eq, so far, the DEPT-OTMS total overall reaction is cooled to-20 ℃ once more, drip the methylene dichloride 1000ml solution of 7-MAC44.2g, 20 ℃ are stirred to mixed acid anhydride and 7-MAC completely dissolve; Add entry 1000ml, separatory, organic layer saturated sodium bicarbonate 500ml, each washing of water 500ml once, anhydrous sodium sulfate drying is taken off solvent under 20 ℃; The ethyl acetate petroleum ether recrystallization gets product TBLZ-ester;

With the TBLZ-ester100g for preparing, be dissolved among the methylene dichloride 300ml, the mixing solutions that adds methyl-phenoxide 200ml and MeOH30ml, 0 ℃ drips trifluoroacetic acid 100ml down, is stirred to raw material and disappears, and adds methyl tertiary butyl ether 1000ml, separate out solid, filter, drying obtains TBLZ-acid;

The TBLZ-acid10g that obtains is dissolved in dimethyl formamide 80ml, drip Sodium isooctanoate 2.92g, 10 ℃ were stirred 1.0 hours, added anhydrous isopropyl alcohol 100ml, stirred 1 hour, separate out a large amount of solids, filter, filter cake washs with Virahol 100ml, then product is placed in the 100ml methyl tertiary butyl ether and stirred 1 hour, filter, the product room temperature is dried, and the room temperature decompressing and extracting is to weight then.

7. preparation method as claimed in claim 1 is characterized in that cefbuperazone is to prepare as follows:

Steps A: with the esterification of D-Threonine

D-Threonine 50g adds anhydrous methanol 100ml, dripping thionyl chloride 30ml under the condition of ice bath, and stirred overnight at room temperature is concentrated into reaction solution dried, is directly used in step B;

The preparation of step B:DEPT-OMe

D-THr-OMe-HCl 30g adds entry 100ml, acetonitrile 50ml, and sodium bicarbonate 46.8g, room temperature slowly drips the acetonitrile 50ml solution of DEPCl 39.8g, adds in 30 minutes; Stirring at room is 1 hour then, and reaction finishes the reaction solution layering, on become the organic layer of acetonitrile, lower floor is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid;

The preparation of step C:DEPT-OMe-OTHP

DEPT-OMe is dissolved among the DMF, add the 10.2g imidazoles, the back slowly drips trimethylchlorosilane 11.95g, and room temperature condition stirred 1 hour down, and reaction finishes, in reaction solution, add entry 200ml, separatory, the dichloromethane extraction of water layer usefulness equivalent 3 times, dried over sodium sulfate organic layer, take off solvent, product can be directly used in step D;

The preparation of step D:DEPT-OTHP

Get DEPT-OMe-OTHP38.5g, add methyl alcohol 200ml stirring and make dissolving, 0 ℃ adds yellow soda ash 10.6g down, stirred 30 minutes; Add the ether of 1g/100ml in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid DEPT-OTHP, directly can be used for next step;

With the DEPT-OTHP37.1g for preparing among the step D, be dissolved in the 1500ml methylene dichloride, add triethylamine 12.1g, be cooled to-20 ℃, drip the dichloromethane solution of Vinyl chloroformate, add 5.4g earlier, stirring at room 1 hour is utilized the high performance liquid chromatography monitoring reaction, calculates the consumption of Vinyl chloroformate with the peak area ratio of raw material according to the product intermediate, the Vinyl chloroformate 6.48g that adds then, so far, the DEPT-OTMS total overall reaction is cooled to-20 ℃ once more, drip the methylene dichloride 1000ml solution of 7-MAC52.3g, 20 ℃ are stirred to mixed acid anhydride and 7-MAC completely dissolve; Add entry 1000ml, separatory, organic layer saturated sodium bicarbonate 500ml, each washing of water 500ml once, anhydrous sodium sulfate drying is taken off solvent under 20 ℃; The ethyl acetate petroleum ether recrystallization gets product TBLZ-ester;

With the TBLZ-ester100g for preparing, be dissolved among the methylene dichloride 300ml, the mixing solutions that adds methyl-phenoxide 200ml and MeOH30ml, 0 ℃ drips trifluoroacetic acid 100ml down, is stirred to raw material and disappears, and adds methyl tertiary butyl ether MTBE1000ml, separate out solid, filter, drying obtains TBLZ-acid;

The TBLZ-acid10g that obtains is dissolved in dimethyl formamide 80ml, drip Sodium isooctanoate 2.92g, 10 ℃ were stirred 1.0 hours, added anhydrous isopropyl alcohol 100ml, stirred 1 hour, separate out a large amount of solids, filter, filter cake washs with Virahol 100ml, then product being placed on the 100ml methyl tertiary butyl ether is to stir 1 hour among the MTBE, filter, the product room temperature is dried, and the room temperature decompressing and extracting is to weight then.

8. preparation method as claimed in claim 1 is characterized in that cefbuperazone is to prepare as follows:

Steps A: with D-Threonine esterification: D-Threonine 50g (0.42mmol), add anhydrous methanol 100ml, dripping thionyl chloride 30ml under the condition of ice bath, stirred overnight at room temperature is concentrated into reaction solution dried, is directly used in step B;

The preparation of step B:DEPT-OMe: D-THr-OMe-HCl 30g, add entry 100ml, acetonitrile 50ml, sodium bicarbonate 46.8g, room temperature slowly drips the acetonitrile 50ml solution of DEPCl 39.8g, adds in 30 minutes; Stirring at room is 1 hour then, and reaction finishes the reaction solution layering, on become the organic layer of acetonitrile, lower floor is a water layer, water layer merges organic layer, anhydrous sodium sulfate drying with acetonitrile 200ml*4 extraction; Filter, decompression is taken off solvent and is obtained white solid;

The preparation of step C:DEPT-OMe-OBz

DEPT-OMe 30.1g is dissolved among the DMF of 150ml, adds salt of wormwood 20.7g, bromobenzyl 20.5g, stirring at room reaction in 5 hours finishes, and adds entry 250ml in reaction solution, with dichloromethane extraction 3 times, merge organic layer, saturated common salt washing 2 times, dried over sodium sulfate, solvent evaporated adds sherwood oil, making ratio is 1g/5ml, ultrasonic 30 minutes, filter, obtain product;

The preparation of step D:DEPT-OBz;

DEPT-OMe-OBz 40.5g stirs and makes it to be dissolved in 2000ml methyl alcohol, and 0 ℃ adds yellow soda ash 10.6g down, stirred 30 minutes; Add the ether of 1g/100ml in reaction solution, separate out solid, filter, the solid drying under reduced pressure gets white solid, directly can be used for next step;

With the DEPT-OBz 39.2g for preparing among the step D, be dissolved in the 1500ml methylene dichloride, add triethylamine 12.1g, be cooled to-20 ℃, drip the dichloromethane solution of Vinyl chloroformate, add 5.4g earlier, stirring at room 1 hour is utilized the high performance liquid chromatography monitoring reaction, calculates the consumption of Vinyl chloroformate with the peak area ratio of raw material according to the product intermediate, the Vinyl chloroformate 6.48g that adds then, so far, the DEPT-OTMS total overall reaction is cooled to-20 ℃ once more, drip the methylene dichloride 1000ml solution of 7-MAC52.3g, 20 ℃ are stirred to mixed acid anhydride and 7-MAC completely dissolve; Add entry 1000ml, separatory, organic layer saturated sodium bicarbonate 500ml, each washing of water 500ml once, anhydrous sodium sulfate drying is taken off solvent under 20 ℃; The ethyl acetate petroleum ether recrystallization gets product TBLZ-ester, yield 89.6%; With the TBLZ-ester100g for preparing, be dissolved among the methylene dichloride 300ml, the mixing solutions that adds methyl-phenoxide 200ml and MeOH30ml, 0 ℃ drips trifluoroacetic acid 100ml down, is stirred to raw material and disappears, and adds methyl tertiary butyl ether MTBE1000ml, separate out solid, filter, drying obtains TBLZ-acid;

The TBLZ-acid10g that obtains is dissolved in dimethyl formamide 80ml, drip Sodium isooctanoate 2.92g, 10 ℃ were stirred 1.0 hours, added anhydrous isopropyl alcohol 100ml, stirred 1 hour, separate out a large amount of solids, filter, filter cake washs with Virahol 100ml, then product being placed on the 100ml methyl tertiary butyl ether is to stir 1 hour among the MTBE, filter, the product room temperature is dried, and the room temperature decompressing and extracting is to weight then.